The goal of the proposed research is to further the understanding of the role of extraembryonic drug metabolism interatogenesis. During the past 2 1/2 years we have developed and used an embryo culture system which incorporates a source of metabolic enzymes (S-9) which acts as a substitute for the maternal liver. Using this system, we have shown that phase I (primarily monooxygenation) reactions can modulate embryonic responses to potential teratogens and confirmed that these pathways are deficient or absent in day 10 rat embryos. We now propose to expand this system to include phase II drug metabolism by incorporating intact hepatic cells. These hepatocytes contain a full compliment of drug metabolizing enzymes and all required confactors and are capable of generating metabolic profiles of the intact animal with a given compound. Teratology is replete with examples of differential respones of strains and species to particular teratogens. A major portion of the metabolic differences between species and strains is accounted for by phase II conjugation reaction. Despite this, there have been no published studies of the modulation of teratogenicity by phase II reactions. We plan to dissect teratogen metabolism using S-9 with specific cofactors for conjugation. Because embryos appear to be metabolically neutral, the use of allospecific hepatocytes in rat embryo culture should provide a powerful tool for predicting teratogenic consequences of exposures of the hepatic donor. This system also enables us to study the teratogenic consequences of prior exposures of 'material' (liver donor) animals to inducers of drug metabolism. It is unique in permitting study of induction free of confounding variables such as maternal stress, drug interaction and nutritional deprivation. We plan to study consequences of acute and chronic exposure of liver donors to ethanol as we have preliminary data indicating significant augmentation of teratogen metabolism by hepatic materials derived from these animals. A dominant goal of teratologists is the development of a screen for human teratogens. By using Primate hepatocytes and in vivo-in vitro comparisons of embryotoxicity we hope to acquire the knowledge and tools for constructing a teratogen screen which can reliably predict the consequences of human exposures.